This invention relates to hydroxamic and carboxylic acid derivatives, and to their use in medicine.
Metalloproteinases, including matrix metalloproteinase (MMP), (human fibroblast) collagenase, gelatinase and TNF convertase (TACE), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-9611209, WO-A-9712902 and WO-A-9719075, the contents of which are incorporated herein by reference. MMP inhibitors may also be useful in the inhibition of other mammalian metalloproteinases such as the adamalysin family (or ADAMs) whose members include TNF convertase (TACE) and ADAM-10, which can cause the release of TNFxcex1 from cells and others, which have been demonstrated to be expressed by human articular cartilage cells and also involved in the destruction of myelin basic protein, a phenomenon associated with multiple sclerosis.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown, such as collagenase, stromelysin and gelatinase, have been shown to inhibit the release of TNF both in vitro and in vivo. See Gearing et al (1994) Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561; GB-A-2268934; and WO-A-9320047. All of these reports inhibitors contain a hydroxamic acid zinc-binding group, as do the imidazole-substituted compounds disclosed in WO-A-9523790. Other compounds that inhibit MMP and/or TNF are described in WO-A-9513289, WO-A-96111209, WO-A-96035687, WO-A-96035711, WO-A-96035712 and WO-A-96035614.
WO-A-9718188 discloses MMP inhibitors of the formula
Ph1xe2x80x94Ph2xe2x80x94Xxe2x80x94(CH2)0-6xe2x80x94(CZ)0-1xe2x80x94(CHR1)0-1xe2x80x94COxe2x80x94NHOH 
wherein Ph1 and Ph2 are each optionally-substituted phenyl; X is absent, O, NH or S; Z is xe2x80x94CONR2R3; and R1 is H, alkyl, alkenyl, OH, optionally-substituted phenyalkyl or phenyl-SO0-2-alkyl, or alkyl-COOR7.
EP-A-0780386 discloses compounds having MMP and TNF inhibitory activity, of the formula
Yxe2x80x94COxe2x80x94CR1R2xe2x80x94CR3R4xe2x80x94S(O)11R5
wherein n i 0, 1 or 2; Y is OH or NHOH; R1 is H or lower alkyl; R2 is H, lower alkyl, heteroalkyl, aryl, aralkyl, arylheteroalkyl, cycloalkyl, heteroaryl, heteroaralkyl, heteroarylheteroalkyl, heterocyclo, heterocyclo-lower alkyl, heterocyclo-lower heteroaryl or NR6R7; R3 is H, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroalkyl or lower alkoxy; R4 is H, lower alkyl, cycloalkyl or cycaloalkylalkyl; and R5 is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.
Compounds of EP-A-0780386 first disclosed in U.S. application No. 8939, filed Dec. 20, 1995, are of the same formula, where R1 is H; R2 is H, lower alkyl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclo or NR6R7; R3 is H, lower alkyl, cycloalkyl, cycloalkylalkyl or aralkyl; R4 is H or lower alkyl; and R5 is lower alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.
U.S. Pat. No. 4,325,964 discloses certain benzhydryl sulphinyl hydroxamates, as having utility in neuropsychic ailments.
Zayed et al, Zeitschrift fxc3xcr Naturforschung (1966)180-182, discloses 3-phenylsulphonylpropanoic acid N-hydroxyamide, as a fungicide.
The invention encompasses novel compounds of formula (I) which are useful inhibitors of matrix metalloproteinases and/or TNFxcex1-mediated diseases, including degenerative diseases and certain cancers.
Novel compounds according to the invention are of the general type represented by formula (I):
Bxe2x80x94Xxe2x80x94(CH2)nxe2x80x94CHR1xe2x80x94(CH2)mxe2x80x94COY xe2x80x83xe2x80x83(I) 
wherein m and n are both independently 0 or 1, but are not both 0;
X is O, NR3 or S(O)0-2;
Y is OR2 or NHOH;
R1 is H or a group (optionally substituted with R9) selected from C1-6 alkyl, C2-6 alkenyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, heterocycloalkyl, C1-6 alkyl-heterocycloalkyl, cycloalkyl and C1-6 alkyl-cycloalkyl;
R2 is H or C1-6 alkyl;
R3 is H, C1-6 alkyl, COR2, CON(R2)2 where each R2 is the same or different, CO2R4 or SO2R4, and
R4 is C1-6 alkyl;
B is C1-6 alkyl-aryl, C1-6 alkyl, cycloalkyl, C1-6 alkyl-cycloalkyl, cycloalkenyl, heterocycloalkenyl, C1-6 alkyl-heteroaryl, heterocycloalkyl, C1-6 alkyl-heterocycloalkyl, aryl or heteroaryl, any of which groups is optionally substituted by a substituent selected from R5, C1-6 alkyl-R5, C2-6 alkenyl-R5, aryl (optionally substituted with R5), aryl-C1-6 alkyl-R5, C1-6 alkyl-aryl (optionally substituted with R5), C1-6 alkyl-heteroaryl (optionally substituted with R5), aryl-C2-6 alkenyl-R7, heteroaryl (optionally substituted with R5), heteroaryl-C1-6 alkyl-R5, cycloalkyl (optionally substituted with R5), benzofused cycloalkyl (optionally substituted with R5), heterocycloalkyl (optionally substituted with R5), benzofused heterocycloalkyl (optionally substituted with R5), and the groups: 
provided that B is not benzhydryl when X is SO and R1 is H;
R5 is C1-6 alkyl, C2-6 alkenyl-R7, halogen, CN NO2, N(R6)2, OR6, COR6, CO2R2, CON(R6)2, NR6R7, S(O)0-2R8 or SO2N(R6)2;
R6 is H or a group selected from C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocycloalkyl and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NR2R8, halogen, CN, SO2NR2R8 or NO2, and for each case of N(R6)2 the R6 groups are the same or different or N(R6)2 is heterocycloalkyl optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NR2R8, halogen, CN, SO2NR2R8 or NO2;
R7 is COR6, CON(R6)2, CO2R8 or SO2R8;
R8 is C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl or C1-6 alkyl-heteroaryl; and R9 is OR6, COR6, CO2R2, CON(R6)2, NR6R7, S(O)0-2R8, SO2N(R6)2, phthalimido, succinimido or the group 
and the salts, solvates, hydrates, protected amino and protected carboxy derivatives thereof;
provided that the compound is not 3-phenylsulfonylpropanoic acid N-hydroxy amide.
Combinations of substituents and/or variables are only permissible if such combinations result in stable compounds.
Preferred compounds of the invention are those wherein any one or more of the following apply:
X is S, SO or SO2;
R1 is H or a group (optionally substituted with R9) selected from C1-6 alkyl, C2-6 , alkenyl, C1-6 alkyl-aryl, C1-6 alkyl-heteroaryl, C1-6 alkyl-heterocycloalkyl and C1-6 alkyl-cycloalkyl;
B is C1-6 alkyl-aryl, C1-6 alkyl, cycloalkyl, cycloalkenyl, heterocycloalkenyl, C1-6 alkyl-heteroaryl, aryl or heteroaryl, any of which groups is optionally substituted by a substituent selected from R5, C1-6 alkyl-R5, aryl (optionally substituted with R5), aryl-C1-6 alkyl-R5, C1-6 alkyl-aryl (optionally substituted with R5), C1-6 alkyl-heteroaryl (optionally substituted with R5), heteroaryl (optionally substituted with R5), heteroaryl-C1-6 alkyl-R5, heteroaryl-C1-6 alkyl-R5 cycloalkyl (optionally substituted with R5), benzofused cycloalkyl (optionally substituted with R5), heterocycloalkyl (optionally substituted with R5), benzofused heterocycloalkyl (optionally substituted with R5 ), and the groups: 
R5 is halogen, CN, NO2, N(R6)2, OR6, COR6, CON(R6)2, NR6R7, or S(O)0-2R8;
R7 is COR6; and
R9 is OR6, CO2R2, CON(R6)2, phthalimido, succinimido or the group 
One group of compounds of the invention is represented by the formula (Ib)
Bxe2x80x94Xxe2x80x94(CH2)nxe2x80x94(CHR1xe2x80x94(CH2)mxe2x80x94COY xe2x80x83xe2x80x83(Ib) 
wherein
m i 0;
n is 1;
X is SO2;
Y is NHOH;
R1 is C1-6 alkyl optionally substituted with R9;
R2 is H or C1-6 alkyl;
B is C1-6 alkyl substituted by R5;
R5 is OR6;
R6 is a group selected from C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocycloalkyl and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NU2R8, halogen, CN, SO2NR2R8 or NO2, and for each case of N(R6)2 the R6 groups are the same or different or N(R6)2 is heterocycloalkyl optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NR2R8, halogen, CN, SO2NR2R8 or NO2;
R7 is COR6, CON(R6)2, CO2R8 or SO2R8;
R8 is C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl or C1-6 alkyl-heteroaryl; and
R9 is phthalimido, succinimido or the group 
and the salts, solvates, hydrates, protected amino and protected carboxy derivatives thereof;
R1 in compounds of formula (Ib) is preferably optionally substituted ethyl, propyl or isopropyl. Especially preferred is where R1 is isopropyl or R1 is propyl substituted by R9, where R9 is in particular the group: 
In compounds of this type each R2 group is preferably methyl.
In compounds of formula (Ib), B is preferably substituted ethyl, propyl or butyl, especially substituted propyl.
One preferred group of compounds of formula (Ib) is where R6 is optionally substituted aryl, heteroaryl, cycloalkyl or C1-6 alkyl-cycloalkyl. Particular R6 groups of interest are optionally substituted phenyl, pyridyl, furanyl, thiophenyl, cyclobutyl, cyclopentyl, cyclohexyl, methyl-cyclobutyl, methyl-cyclopentyl, methyl-cyclohexyl, ethyl-cyclobutyl, ethyl-cyclopenyl or ethyl-cyclohexyl, especially optionally substituted phenyl, pyridyl, cyclohexyl or methyl-cyclohexyl.
When R6 in compounds of formula (Ib) is substituted, it is preferably substituted by R8, particularly where R8 is phenyl, OR8, particularly where OR8 is OCH3, F, Cl, Br, I or CN, especially phenyl, OCH3 or Cl.
In another embodiment of the invention, a particular group of compounds is represented by the formula (Ic):
Bxe2x80x94Xxe2x80x94(CH2)nxe2x80x94CHR1xe2x80x94(CH2)mxe2x80x94COY xe2x80x83xe2x80x83(Ic) 
where
m is 0;
n is 1;
X is SO2;
Y is NHOH;
R1 is C1-6 alkyl substituted with R9;
R2 is H or C1-6 alkyl;
B is aryl or heteroaryl, either of which is optionally substituted by a substituent selected from R5, C1-6 alkyl-R5, C2-6 alkenyl-R5, aryl (optionally substituted with R5), aryl-C1-6 alkyl-R5, C1-6 alkyl-aryl (optionally substituted with R5), C1-6 alkyl-heteroaryl (optionally substituted with R5), aryl-C2-6 alkenyl-R7, heteroaryl (optionally substituted with R5), heteroaryl-C1-6 alkyl-R5, cycloalkyl (optionally substituted with R5), benzofused cycloalkyl (optionally substituted with R5), heterocycloalkyl (optionally substituted with R5), benzofused heterocycloalkyl (optionally substituted with R5), and the groups: 
R5 is C1-6 alkyl, C2-6 alkenyl-R7, halogen, CN NO2, N(R6)2, OR6, COR6, CO2R2, CON(R6)2, NR6R7, S(O)0-2R8 or SO2N(R6)2;
R6 is H or a group selected from C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocycloalkyl and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NR2R8, halogen, CN, SO2NR2R8 or NO2, and for each case of N(R6)2 the R6 groups are the same or different or N(R6)2 is heterocycloalkyl optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2 R8, NR2R8, halogen, CN, SO2NR2R8 or NO2;
R7 is COR6, CON(R6)2, CO2R8 or SO2R8;
R8 is C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl or C1-6 alkyl-heteroaryl; and
R9 is phthalimido, succinimido or the group 
and the salts, solvates, hydrates protected amino and protected carboxy derivatives thereof;
R1 in compounds of formula (Ic) is preferably substituted ethyl or propyl.
Each R2 group is in particular methyl.
In compounds of formula (Ic), B is especially optionally substituted phenyl, furanyl, thiophenyl or pyridyl or pyridyl-N-oxide, especially optionally substituted phenyl, pyridyl or pyridyl-N-oxide.
One preferred group of compounds of formula (Ic) is where R5 is OR6 or COR6. R6 in compounds of this type is in particular optionally substituted C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl or C1-6 alkyl-heteroaryl, especially optionally substituted C1-6 alkyl, aryl, heteroaryl or C1-6 alkyl-heteroaryl. Particular R6 groups are optionally substituted methyl, phenyl, furanyl, thiophenyl, pyridyl, pyridyl-N-oxide, methyl-pyridyl, ethyl-pyridyl methyl-furanyl, ethyl-furanyl, methyl-thiophenyl or ethyl-thiophenyl, especially optionally substituted methyl, phenyl, thiophenyl, pyridyl, pyridyl-N-oxide, or methyl-pyridyl.
When R6 in compounds of formula (Ic) is substituted, it is in particular substituted by OR8, particularly where OR8 is OCH3, F, Cl, Br, I or CN especially F, Cl or CN.
A further group of compounds of the invention is represented by the formula (Id)
Bxe2x80x94Xxe2x80x94(CH2)nxe2x80x94CHR1xe2x80x94(C2)mxe2x80x94COY xe2x80x83xe2x80x83(Id) 
wherein
m is 0;
n is 1;
Y is SO2;
Y is NHOH;
R1 is H or a group (optionally substituted with R9) selected from C1-6 alkyl, C2-6 alkenyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, heterocycloalkyl, C1-6 alkyl-heterocycloalkyl, cycloalkyl and C1-6 alkyl-cycloalkyl;
R2 is H or C1-6 alkyl;
B is aryl or heteroaryl, either of which is substituted by R5;
R2 is H or C1-6 alkyl;
R5 is OR6a, S(O)1-2R8 or NR6R7;
R6 is H or a group selected from C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocycloalkyl and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NR2R8, halogen, CN, SO2NR2R8 or NO2;
R6ais selected from C1-6 alkyl-heteroaryl, C1-6 alkyl-cycloalkyl and C1-6 alkyl-heterocycloalkyl wherein said group is optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2 R8, NR2R8, halogen, CN, SO2NR2R8 NO2, or R6a is C1-6 alkyl-aryl substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NR2R8, halogen, CN, SO2NR2R8 or NO2;
R7 is CON(R6)2, or SO2R8;
R8 is C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl or C1-6 alkyl-heteroaryl; and
R8 or OR6, COR6, CO2R2, CON(R6)2, NR6R7, S(O)0-2R8,SO2N(R6)2, phthalimido, succinimido or the group. 
and the salts, solvates, hydrates, protected amino and protected carboxy derivatives thereof;
R1 in compounds of formula (Id) is in particular optionally substituted C1-6 alkyl. Especially preferred is isopropyl.
In compounds of formula (Id), B is preferably substituted aryl, especially substituted phenyl.
A preferred group of compounds has the formula (Ic) wherein R5 is NR6R7 . Especially preferred is where R7 is CON(R6)2. In compounds of this type, R6 is in particular a hydrogen atom or a C1-6 alkyl group, especially a hydrogen atom.
Another group of compounds of the invention is represented by the formula (Ie):
Bxe2x80x94Xxe2x80x94(CH2)2xe2x80x94CHR1xe2x80x94(CH2)mxe2x80x94COY xe2x80x83xe2x80x83(Ie) 
wherein
m is 0;
n is 1;
X is SO2;
Y is NHOH;
R1 is aryl or heteroaryl, either of which is optionally substituted with R9;
R2 is H or C1-6 alkyl;
B is heteroaryl optionally substituted by a substituent selected from R5, C1-6 alkyl-R5, C2-6 alkenyl-R5, aryl (optionally substituted with R5), aryl-C1-6 alkyl-R5, C1-6 alkyl-aryl (optionally substituted with R5), C1-6 alkyl-heteroaryl (optionally substituted with R5), aryl-C2-6 alkenyl-R7, heteroaryl (optionally substituted with R5), heteroaryl-C1-6 alkyl-R5, cycloalkyl (optionally substituted with R5 ), benzofused cycloalkyl (optionally substituted with R5), heterocycloalkyl (optionally substituted with R5), benzofused heterocycloalkyl (optionally substituted with R5), and the groups: 
R5 is C1-6 alkyl, C2-6 alkenyl-R7, halogen, CN, NO2, N(R6)2, OR6, COR6, CO2R2, CON(R6)2, NR6R7, S(O)0-2R8 or SO2N(R6)2;
R6 is H or a group selected from C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl, C1-6 alkyl-heteroaryl, cycloalkyl, C1-6 alkyl-cycloalkyl, heterocycloalkyl, and C1-6 alkyl-heterocycloalkyl, wherein said group is optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NR2R8, halogen, CN SO2NR2R8 or NO2, and for each case of N(R6)2 the R6 groups are the same or different or N(R6)2 is heterocycloalkyl optionally substituted with R8, COR8, SO0-2R8, CO2R8, OR8, CONR2R8, NR2R8, halogen, CN, SO2NR2R8 or NO2;
R7 is COR6, CON(R6)2, CO2R8 or SO2R8;
R8 is C1-6 alkyl, aryl, C1-6 alkyl-aryl, heteroaryl or C1-6 alkyl-heteroaryl; and
R9 is OR6, COR6, CO2R2, CON(R6)2, NR6R7, S(O)0-2R8, SO2N(R6)2, phthalimido, succinimido or the group 
and the salts, solvates, hydrates, processed amino and protected carboxy derivatives thereof:
R1 in compounds of formula (Ie) is in particular optionally substituted aryl, R1 is especially phenyl.
In compounds of formula (Ie), B is in particular optionally substituted furanyl, thiophenyl or pyridyl, especially optionally substituted thiophenyl. Especially preferred is where B is thiophenyl.
The compounds of the Examples are particularly preferred.
It will be appreciated that the compounds according to the invention can contain one or more asymmetrically substituted carbon atoms. The presence of one or more of these asymmetric centres in a compound of formula (I) can give rise to stereoisomers, and in each case the invention is to be understood to extend to all such stereoisomers, including enantiomers and diastereomers, and mixtures including racemic mixtures thereof.
As used in this specification, alone or in combination, the term xe2x80x9cC1-6 alkylxe2x80x9d refers to straight or branched chain alkyl moiety having from one to six carbon atoms, including for example, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
The term xe2x80x9cC2-6 alkenylxe2x80x9d refers to a straight or branched chain alkyl moiety having two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1- propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl etc.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a saturated alicyclic moiety having from three to six carbon atoms and includes for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. xe2x80x9cBenzofused cycloalkylxe2x80x9d includes indanyl and tetrahydronaphthyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to a saturated heterocyclic moiety having from three to six carbon atoms and one or more heteroatom from the group N, O, S and includes for example, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl and the like. xe2x80x9cBenzofused heterocycloalkylxe2x80x9d includes indolinyl and tetrahydroquinolinyl.
The term xe2x80x9ccycloalkenylxe2x80x9d refers to an alicyclic moiety having from three to six carbon atoms and having in addition one double bond. This term would include for example cyclopentenyl or cyclohexenyl.
The term xe2x80x9cheterocycloalkenylxe2x80x9d refers to an alicyclic moiety having from three to six carbon atoms and one or more heteroatoms from the group N, O, S and having in addition one double bond. This term includes, for example, dihydropyranyl.
The term xe2x80x9carylxe2x80x9d means an optionally substituted phenyl or naphthyl group with the substituent(s) being selected, for example, from halogen, trifluoromethyl, C1-6 alkyl, alkoxy, phenyl and the like.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic ring systems of five to ten atoms of which at least one atom is selected from O, N and S, and includes for example furanyl, thiophenyl, pyridyl, indolyl, quinolyl and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to a straight chain or branched chain alkoxy group containing a maximum of six carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
The term xe2x80x9cprotected aminoxe2x80x9d and xe2x80x9cprotected carboxyxe2x80x9d means amino and carboxy groups which can be protected in a manner familiar to those skilled in the art. For example, an amino group can be protected by a benzyloxycarbonyl, tert-butoxycarbonyl, acetyl or like group, or may be in the form of a phthalimido or like group. A carboxyl group can be protected in the form of a readily-cleavable ester such as the methyl, ethyl, benzyl or tert-butyl ester.
Salts of compounds of formula (I) include pharmaceutically-acceptable salts, for example acid addition salts derived from inorganic or organic acids, such as hydrochlorides, hydrobromides, p-toluenesulphonates, phosphates, sulphates, perchlorates, acetates, trifluoroacetates, propionates, citrates, malonates, succinates, lactates, oxalates, tartrates and benzoates.
Salts may also be formed with bases. Such salts include salts derived from inorganic or organic bases, for example alkali metal salts such as magnesium or calcium salts, and organic amine salts such as morpholine, piperidine, dimethylamine or diethylamine salts.
When the xe2x80x9cprotected carboxyxe2x80x9d group in compounds of the invention is an esterified carboxyl group, it may be a metabolically-labile ester of formula CO2R10 where R10 may be an ethyl, benzyl, phenethyl, phenylpropyl, xcex1- or xcex2-naphthyl, 2,4-dimethylphenyl, 4-tert-butylphenyl, 2,2,2-trifluoroethyl, 1-(benzyloxy)benzyl, 1-(benzyloxy)ethyl, 2- methyl-1-propionyloxypropyl, 2,4,6-trimethylbenzyloxymethyl or pivaloylmethyl group.
Compounds of the general formula (I) may be prepared by any suitable method known in the art and/or by the following processes.
It will be appreciated that, where a particular stereoisomer of formula (I) is required, the synthetic processes described herein may be used with the appropriate homochiral starting material and/or isomers maybe resolved from mixtures using conventional separation technique (e.g. HPLC).
The compounds according to the invention may be prepared by the following process. In the description and formulae below the groups R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, B, X and Y are defined above, except where otherwise indicated. It will be appreciated that functional groups, such as amino, hydroxyl or carboxyl groups, present in the various compounds described below, and which it is desired to retain, may need to be protected from before any reaction is initiated. In such instances, removal of the protecting group may be the final step in a particular reaction. Suitable protecting groups for such functionality will be apparent to those skilled in the art. For specific details see Greene et al., xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, Wiley Interscience.
A process for preparing compounds of general formula (I) comprises alkylating a compound of formula Bxe2x80x94XH (II) wherein B and X are as previously defined, with an alkylating agent of formula Zxe2x80x94(CH2)nxe2x80x94CHR1 xe2x80x94(CH2)mxe2x80x94Coy (III), using for example an amine base, such as triethylamine in N,N-dimethylformamide (DMF); or (when m=0) an acrylate of formula CH2=CR1xe2x80x94COY (IV) wherein R1 and Y are as defined previously and Z represents a suitable leaving group (e.g. a halogen such as bromine, or an alkylsulphonate ester such as methanesulphonate).
Alkylating agents (III) can be obtained in chiral or racemic form. Many of these derivatives can be readily obtained from commercially available starting materials using methods known to those skilled in the art (see WO-A-9005719).
Acrylates of formula (IV) may be prepared by the Mannich reaction (i.e. with paraformaldehyde and piperidine in a suitable organic solvent, such as 1,4-dioxane) on a dicarboxylic acid of general formula HO2Cxe2x80x94CHR1xe2x80x94CO2H (V). This reaction involves an eliminative decarboxylation step resulting in the formation of an xcex1, xcex2-unsaturated carboxylic acid (i.e., where Y=OH) directly. This carboxylic acid can then be elaborated using standard chemistry, known to those skilled in the art, to provide ester (Y=OR2) or hydroxamides (NHOR11) where R11 is a suitable protecting group such as benzyl, tert-butyl or tert-butyldimethylsilyl (TBDMS).
Dicarboxylic acids of formula (V) may be prepared by the alkylation of, for instance, diethyl malonate with an alkylating agent of formula R1xe2x80x94Z (VI), wherein Z is as defined above, followed by hydrolysis under basic conditions.
Compounds of formula (II) in which B includes includes an aryl, heteroaryl, functional or other group as a substituent on a core part thereof (B1), may be prepared by palladium-catalysed coupling of an aryl, heteroaryl, functionalising or other compound with a compound of general formula Axe2x80x94B1xe2x80x94XR12 (VII) where R12 is a suitable protecting group such as a methyl, tert-butyl, benzyl or trityl, and A is a halide such as iodide, bromide or, in some instances, chloride. This is followed by removal of any protecting groups.
Many such palladium-catalysed coupling reactions are known to those skilled in the art and can provide compounds of formula (II) bearing substituents described by R5 such as COR6 , CO2R2 or CON(R6)2 as well as aryl, heteroaryl, alkenyl or alkyl groups optionally substituted by R5. Other groups described by B and/or R5 can be introduced by standard chemical transformations known to those skilled in the art.
Many compounds of general formulae (II), (VI) and (VII) are commercially available or may be prepared, by standard aromatic, heteroaromatic or other chemistry known to those skilled in the art, from commercially-available materials.
If required, intermediates of general formulae (VIII) and (IX) 
may be prepared by Friedel-Crafts acylation of a simple aromatic system Ph-XH(X) with phthalic or maleic anhydride, followed by treatment with a hydrazine of general formula H2Nxe2x80x94NHR2 (XI).
Compounds of formula (I) may also be prepared by interconversion of other compounds of formula (I). Thus, for example, a compound of formula (I) wherein R1 is a C1-6 alkyl group may be prepared by hydrogenation (using palladium on carbon in suitable solvent, such as an alcohol, e.g. ethanol) of a compound of formula (I) wherein R1 is a C2-6 alkenyl group. Alternatively, acetylsulfanyl-tert-butyl esters (XII), where R1 is in general one of the groups isopropyl, propylsuccinimide or propylhydantoin, may be reaction with bromides (XI) (commercially available or prepared according to the literature or via the methods described below) for example, in methanol with sodium bis(trimethylsilyl)amide to give sulfanyl-tert-butyl esters of general formula (I). These may be deprotected using trifluoroacetic acid to afford the desired sulfanyl-acids of general formula (I), as shown in scheme A. 
Further, a compound of formula (I) where X is S(O)1-2 may be prepared by oxidation in a compound of formula (I) wherein X is S, for example using Oxone(copyright) in methanol/water. Carboxylic acids of general formula (I) (Y=OH) may be converted to other compounds of formula (I) such as esters (Y=OR2) or hydroxamic acids (Y=NHOH) using methods known to those skilled in the art. For example, the acids of general formula (I) may be reacted with oxalyl chloride and catalytic DMF in dichloromethane to afford the corresponding acid chlorides which are treated with hydroxylamine in THF/water. Alternatively, the acids of general formula (I) may be coupled with O-tert-butyldimethylsilyl-protected hydroxylamine using, for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-dimethylaminopyridine in dichloromethane and the resulting products deprotected using, for example, either tetrabutylammonium fluoride in dichloromethane or hydrogen chloride in diethyl ether.
These interconversions of compounds of general formula (I) are illustrated in the general scheme B. 
Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in known manner, into the pure final product or intermediates, for example by chromatography, distillation, fractional crystallization, or by formation of a salt if appropriate or possible under the circumstances.
The compounds according to the invention exhibit in vitro inhibiting activities with respect to the stromelysins, collagenases and gelatinases. Compounds according to the invention also exhibit in vitro inhibition of TNF release, TNF receptor shedding, IL-6 receptor shedding and L-selectin shedding.
The 80 kD TNF receptor (TNFR80) is proteolytically cleaved at the cell surface (shed), releasing a soluble ligand-binding receptor fragment. Interestingly, the processing of TNFxcex1 and shedding of TNFR80 have been demonstrated to occur concurrently in activated T-cells, arousing speculation that a common protease may be involved. It has been shown by Crowe et al, J. Exp. Med., (1995) 181:1205, that a synthetic inhibitor of TNF processing also blocks the shedding of TNFR80, suggesting that these processes may be coordinately regulated during T-cell activation. Notably, the protease cleavage site in pro-TNF(Ala-Val) is also present in the extracellular domain of TNFR80 (Ala213-Val214) at a site consistent with the observed molecular weight of the shed receptor fragment. Thus, metalloproteinase inhibitors may offer protection from the deleterious systemic effects of TNFxcex1 at two levels simultaneously, firstly by preventing the release of soluble TNFxcex1, and secondly by blocking the accumulation of shed TNFR80.
Synergistically with TNF, metalloproteinase inhibitors also inhibit the release of APO-1/Fas (CD96) ligand (APO-1L) which induces apoptosis in sensitive target cells. The shedding APO-1/Fas (CD95), a type I transmembrane glycoprotein belonging to the nerve growth factor/TNF receptor sub-family is also blocked by known metalloproteinase inhibitors but not by common inhibitors of serine/cysteine proteases; see Mariani et al, Eur. J. Immunol., (1995) 25:2303. Several other important receptors expressed by activated T- and B-cells have also been demonstrated to be shed from the cell surface by the action of metalloproteinases. These enzymes, collectively known as sheddases, provide new targets for inhibitors of metalloproteinases, including compounds of the present invention.
The activity and selectivity of the compounds may be determined by use of the appropriate enzyme inhibition test, for example as described in Examples A-M, below. Certain compounds of this invention have selective inhibitory activity, in particular inhibition of MMP substantially without inhibition of TNF release and related activities as defined above. This may be of particular value where such activities are associated with reduced side-effects.
This invention also relates to a method of treatment for patients (including man and/or mammalian animals raised in the dairy, meat or fur industries or as pets), suffering from disorders or diseases which can be attributed to stromelysin as previously described, and more specifically, a method of treatment involving the administration of the matrix metalloproteinase inhibitors of formula (I) as the active constituents.
Accordingly, the compounds of formula (I) can be used among other things in the treatment of osteoarthritis and rheumatoid arthritis, and in diseases and indications resulting from the over-expression of these matrix metalloproteinases such as found in certain metastatic tumour cell lines.
As mentioned above, compounds of formula (I) are useful in human or veterinary medicine since they are active as inhibitors of TNF and MMPs. Accordingly in another aspect, this invention concerns:
a method of management (by which in meant treatment of prophylaxis) of disease or conditions mediated by TNF and/or MMPs in mammals, in particular in humans, which method comprises administering to the mammal an effective, amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof, and
a compound of formula (I) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by TNF and/or MMPs; and
the use of a compound of formula (I) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by TNF and/or MMPs.
The disease or conditions referred to above include inflammatory diseases, autoimmune diseases cancer, cardiovascular diseases, diseases involving tissue breakdown such as rheumatoid arthritis, osteoarthritis, osteoporosis, neurodegeneration, Alzheimer""s disease, stroke, vasculitis, Crohn""s disease, ulcerative colitis, multiple sclerosis, periodontitis, gingivitis and those involving tissue breakdown such as bone resorption, haemorrhage, coagulation, acute phase response, cachexia and anorexia, acute infections, HIV infections, fever, shock states, graft versus host reactions, dermatological conditions, surgical wound healing, psoriasis, atopic dermatitis, epidermolysis bullosa, tumour growth, angiogenesis and invasion by secondary metastases, ophthalmological disease, retinopathy, corneal ulceration, reperfusion injury, migraine, meningitis, asthma, rhinitis, allergic conjunctivitis, eczema, anaphylaxis, restenosis, congestive heart failure, endometriosis, atherosclerosis, endosclerosis and aspiring-independent anti-thrombosis.
For the treatment of rheumatoid arthritis, osteoarthritis, and in diseases and indications resulting from the over-expression of matrix metalloendoproteinases such as found in certain metastatic tumour cell lines or other diseases mediated by the matrix metalloendoproteinases or increased TNF production, the compounds of formula (I) may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats etc) the compounds of the invention are effective in the treatment of humans.
The pharmaceutical composition containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to protect pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874, to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules where in the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate polyvinyl-pyrrolidine, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene with partial esters derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient of admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified, for example sweetening, flavouring and colouring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soya bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be in a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mon- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of formula (I) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, jellies, solutions or suspensions, etc containing the compounds of Formula (I) are employed. For the purposes of this specification, topical application includes mouth washes and gargles.
Dosage levels of the order of from about 0.05 mg to about 40 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 2.5 mg to about 7 g per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound for kilogram of body weight per day (about 0.5 mg to about 3.5 g per patient per day).
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may vary from about 5 to about 95% of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of the active ingredient.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.